Cell cycle and diseases

细胞周期与疾病

基本信息

批准号：
13043012
负责人：
KOHSAKA Hitoshi
金额：
$ 47.74万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2005
项目状态：
已结题

项目摘要

Intra-articular gene transfer of cyclin-dependent kinase inhibitors (CDKI) to suppress synovial cell cycling has shown efficacy in treating animal models of rheumatoid arthritis (RA). CDKIs also modulate immune function via a CDKindependent pathway. Accordingly, systemic administration of small molecules that inhibit. CDK might ameliorate arthritis. In order to address this issue, alvocidib (flavopiridol), known to be tolerated clinically for treating cancers, and also a newly synthesized CDK4/6-selective inhibitor were tested for anti-arthritic effects. In vitro, they inhibited proliferation of human and mouse synovial fibroblasts without inducing apoptosis. In vivo, treatment of collagen-induced arthritis (CIA) mice with alvocidib suppressed synovial hyperplasia and joint destruction while serum concentrations of anti-type II collagen (Cll) antibodies and proliferative responses to Cll were maintained. Treatment was effective even when therapeutically administered. Treated mice developed arthritis after termination of treatment. Thus, immune responses to Cll were unimpaired. The same treatment ameliorated arthritis induced by K/BxN serum transfer to lymphocyte-deficient mice. Similarly, the CDK4/6-selective inhibitor suppressed CIA. Both small molecule (sm) CDK inhibitors were effective in treating animal models of RA not by suppressing lymphocyte function. We believe that smCDK inhibitors hold promise as a new class of anti-rheumatic drugs that inhibit a distinct phase of rheumatoid pathogenesis

细胞周期蛋白依赖性激酶抑制剂 (CDKI) 的关节内基因转移可抑制滑膜细胞周期，在治疗类风湿性关节炎 (RA) 动物模型中显示出疗效。 CDKI 还通过 CDK 独立途径调节免疫功能。因此，全身施用抑制的小分子。 CDK 可能会改善关节炎。为了解决这个问题，我们测试了临床上已知可耐受用于治疗癌症的alvocidib（flavopiridol）以及新合成的CDK4/6选择性抑制剂的抗关节炎作用。在体外，它们抑制人和小鼠滑膜成纤维细胞的增殖而不诱导细胞凋亡。在体内，用alvocidib治疗胶原诱导性关节炎（CIA）小鼠可抑制滑膜增生和关节破坏，同时维持抗II型胶原（Cll）抗体的血清浓度和对Cll的增殖反应。即使进行治疗，治疗也是有效的。治疗结束后，接受治疗的小鼠出现关节炎。因此，对 Cll 的免疫反应未受影响。相同的治疗改善了将 K/BxN 血清转移到淋巴细胞缺陷小鼠中诱导的关节炎。同样，CDK4/6 选择性抑制剂抑制 CIA。两种小分子 (sm) CDK 抑制剂均可有效治疗 RA 动物模型，而不是通过抑制淋巴细胞功能。我们相信 smCDK 抑制剂有望成为一类新型抗风湿药物，可抑制类风湿发病机制的不同阶段

项目成果

期刊论文数量（96）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cyclin-dependent kinase 4/6 directly modulates expression of rheumatoid inflammatory mediators in retinoblastoma protein-dependent and independent pathways

细胞周期蛋白依赖性激酶 4/6 直接调节视网膜母细胞瘤蛋白依赖性和独立通路中类风湿炎症介质的表达

DOI：
发表时间：
期刊：
Arthritis Rheum. (in press)
影响因子：
0
作者：
Nonomura Y;Nagasaka K;Hagiyama H;Sekine C;Nanki T;Tamamori-Adachi M;Miyasaka N;Kohsaka N.
通讯作者：
Kohsaka N.

Terada Y., Inoshita S., Hanada S.et al.: "Hyperosmolality activates Akt and regulates apoptosis in renal tubular cells"Kidney International. 60(2). 553-567 (2001)

Terada Y.、Inoshita S.、Hanada S.等人：“高渗透压激活 Akt 并调节肾小管细胞凋亡”Kidney International。